Protein arginine methyltransferase 1 (PRMT1) represses MHC II transcription in macrophages by methylating CIITA

Zhiwen Fan,Ping Li,Xiaoyan Wu,Yong Xu,Jianfei Li,Qing Ye,Huihui Xu

doi:10.1038/srep40531

Abstract

Efficient presentation of alien antigens triggers activation of T lymphocytes and robust host defense against invading pathogens. This pathophysiological process relies on the expression of major histocompatibility complex (MHC) molecules in antigen presenting cells such as macrophages. Aberrant MHC II transactivation plays a crucial role in the pathogenesis of atherosclerosis. Class II transactivator (CIITA) mediates MHC II induction by interferon gamma (IFN-γ). CIITA activity can be fine-tuned at the post-translational level, but the mechanisms are not fully appreciated. We investigated the role of protein arginine methyltransferase 1 (PRMT1) in this process. We report here that CIITA interacted with PRMT1. IFN-γ treatment down-regulated PRMT1 expression and attenuated PRMT1 binding on the MHC II promoter. Over-expression of PRMT1 repressed MHC II promoter activity while PRMT1 depletion enhanced MHC II transactivation. Mechanistically, PRMT1 methylated CIITA and promoted CIITA degradation. Therefore, our data reveal a previously unrecognized role for PRMT1 in suppressing CIITA-mediated MHC II transactivation.

Highlights

Antigen presentation by antigen presenting cells (APCs) represents a key step in T lymphocyte activation, a pathophysiological process that depends on the expression of class II major histocompatibility complex (MHC II) molecules[6,7]
Class II transactivator (CIITA) dependent MHC II transcription contributes to T lymphocyte activation and adaptive immunity
We report here that the protein arginine methyltransferase Protein arginine methyltransferase 1 (PRMT1) represses MHC II transcription in macrophages by methylating CIITA

Summary

Introduction

Antigen presentation by antigen presenting cells (APCs) represents a key step in T lymphocyte activation, a pathophysiological process that depends on the expression of class II major histocompatibility complex (MHC II) molecules[6,7]. MHC II is constitutively expressed in certain types of APCs (e.g., dendritic cells), but can be induced in other APCs (e.g., macrophages) by the pro-inflammatory cytokine interferon gamma (IFN-γ) at the transcriptional level[8]. Histone deacetylase 2 (HDAC2) mediated deacetylation of CIITA targets CIITA for proteasomal degradation and attenuates MHC II transactivation[12]. PRMT1 has been shown to repress NF-κB-mediated inflammation by methylating and preventing RelA from binding to target genes[16]. PRMT1-mediated methylation of TNF receptor-associated factor 6 (TRAF6), an integral part of the signalosome that activates NF-κB, represses inflammation[17]. In the present study we investigated the involvement of PRMT1 in IFN-γ-induced, CIITA-dependent MHC II transactivation in macrophages. Our data demonstrate that PRMT1 represses MHC II transcription in macrophages by methylating CIITA and promoting CIITA degradation

Methods

Results

Conclusion